A Key Role for CC Chemokine Receptor 4 in Lipopolysaccharide-induced Endotoxic Shock

doi:10.1084/jem.191.10.1755

Published online 15 May 2000.

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© The Rockefeller University Press, 0022-1007/2000/5/1755/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 10, May 15, 2000 1755-1764

Original Article

A Key Role for CC Chemokine Receptor 4 in Lipopolysaccharide-induced Endotoxic Shock

Yolande Chvatchko^a, Arlene J. Hoogewerf^a, Alexandra Meyer^a, Sami Alouani^a, Pierre Juillard^a, Raphaele Buser^a, Francois Conquet^a, Amanda E.I. Proudfoot^a, Timothy N.C. Wells^a, and Christine A. Power^a
^a Serono Pharmaceutical Research Institute, 1228 Plan-les-Ouates/Geneva, Switzerland

Correspondence to: Yolande Chvatchko, Serono Pharmaceutical Research Institute, 14, chemin des Aulx, 1228 Plan-les-Ouates/Geneva, Switzerland. Tel:41-22-7069-666 Fax:41-22-7069-718 E-mail:yolande.chvatchko{at}serono.com.

CC chemokine receptor (CCR)4, a high affinity receptor for theCC chemokines thymus and activation-regulated chemokine (TARC)and macrophage-derived chemokine (MDC), is expressed in thethymus and spleen, and also by peripheral blood T cells, macrophages,platelets, and basophils. Recent studies have shown that CCR4is the major chemokine receptor expressed by T helper type 2(Th2) polarized cells. To study the in vivo role of CCR4, wehave generated CCR4-deficient (CCR4^-/-) mice by gene targeting.CCR4^-/- mice developed normally. Splenocytes and thymocytesisolated from the CCR4^-/- mice failed to respond to the CCR4ligands TARC and MDC, as expected, but also surprisingly didnot undergo chemotaxis in vitro in response to macrophage inflammatoryprotein (MIP)-1 ${alpha}$ . The CCR4 deletion had no effect on Th2 differentiationin vitro or in a Th2-dependent model of allergic airway inflammation.However, CCR4^-/- mice exhibited significantly decreased mortalityon administration of high or low dose bacterial lipopolysaccharide(LPS) compared with CCR4^+/+ mice. After high dose LPS treatment,serum levels of tumor necrosis factor ${alpha}$ , interleukin 1ß,and MIP-1 ${alpha}$ were reduced in CCR4^-/- mice, and decreased expressionof MDC and MIP-2 mRNA was detected in peritoneal exudate cells.Analysis of peritoneal lavage cells from CCR4^-/- mice by flowcytometry also revealed a significant decrease in the F4/80⁺cell population. This may reflect a defect in the ability ofthe CCR4^-/- macrophages to be retained in the peritoneal cavity.Taken together, our data reveal an unexpected role for CCR4in the inflammatory response leading to LPS-induced lethality.

Key Words: CC chemokine receptor 4, lipopolysaccharide, endotoxic shock,F4/80 antigen, T helper type 2 cells

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